1. Pediatric Oncology Subcommittee of the Oncologic Drugs Advisory Committee July 15, 2003 Steven Hirschfeld, MD PhD CAPT USPHS Division of Oncology Drug Products & Division of Pediatric Drug Development Center for Drug Development and Research Food and Drug Administration

2. Meetings of the Pediatric Subcommittee of the Oncologic Drugs Advisory Committee September 2000 –Discussion of methods that may be used to describe and link tumor types April 2001 –Hematologic tumors and the Pediatric Rule June 2001 –Solid tumors and central nervous system malignancies and the Pediatric Rule

3. Meetings of the Pediatric Subcommittee of the Oncologic Drugs Advisory Committee November 2001 –Study designs and extrapolation October 2002 –Timing of pediatric clinical studies and criteria for initiating studies with investigational agents March 2003 –Pediatric information in oncology product labeling

4. July 2003-Risk Assessment FDA General Perspective on Risk Assessment Discussion of proposed change in product package insert for 6-mercaptopurine to include pharmacogenetic screening recommendation Discussion of regulatory and patient protection procedures and perceived barriers to the implementation of multinational studies in pediatric oncology

5. 6-Mercaptopurine 6-mercaptopurine was synthesized by Elion and Hitchings to inhibit cell growth and it was approved by the FDA for treatment of acute leukemia in 1953 Has been used as component of anti- leukemia therapy in pediatric oncology clinical trials for 50 years.

6. Current Product Package Insert INDICATIONS AND USAGE PURINETHOL (mercaptopurine) is indicated for remission induction and maintenance therapy of acute lymphatic leukemia. Note that product package insert uses the terms lymphatic, lymphocytic and lymphoblastic to refer to the same set of diseases

7. Current Product Package Insert CAUTION PURINETHOL (mercaptopurine) is a potent drug. It should not be used unless a diagnosis of acute lymphatic leukemia has been adequately established and the responsible physician is knowledgeable in assessing response to chemotherapy.

8. Current Product Package Insert Warning Section: There are individuals with an inherited deficiency of the enzyme thiopurine methyltransferase (TPMT) who may be unusually sensitive to the myelosuppressive effects of mercaptopurine and prone to developing rapid bone marrow suppression following the initiation of treatment. Substantial dosage reductions may be required to avoid the development of life-threatening bone marrow suppression in these patients. This toxicity may be more profound in patients treated with concomitant allopurinol. This problem could be exacerbated by coadministration with drugs that inhibit TPMT, such as olsalazine, mesalazine, or sulphasalazine.

9. Current Product Package Insert The Dosage Section states: PURINETHOL is administered orally. The dosage which will be tolerated and be effective varies from patient to patient, and therefore careful titration is necessary to obtain the optimum therapeutic effect without incurring excessive, unintended toxicity. Once a complete hematologic remission is obtained, maintenance therapy is considered essential. Maintenance doses will vary from patient to patient.

10. Estimated number of affected patients with TMPT deficiency and acute lymphoblastic leukemia Estimated 3250 children per year in the United States diagnosed with leukemia of which 2400 (~75%) have acute lymphoblastic leukemia Based on frequency of 0.3% homozygous deficiency and assuming proportionate representation in the leukemic population as in the populations previously studied, an estimated 8 children per year would be affected. Based on frequency of 10% heterozygous deficiency and with similar assumptions as above, an estimated 240 children per year would be affected.

11. Dose adjustment Data on dose adjustment –For homozgous patients data are limited and variable –For heterozygous reduction no data exist from a cooperative group prospective clinical trial on what dosing regimen is appropriate to use

12. Questions regarding assessment of 6- mercaptopurine metabolism Highly variable absorption of oral drug Rapid metabolism in blood (product label states half life of about 20 minutes in children) Red cell test for 6-thioguanine nucleotides uses only living red blood cells- may not represent true tissue levels

13. Questions regarding genetic testing Which mutant alleles are captured by which tests? Will different tests have different results? Should testing procedures receive formal FDA approval?

14. Evaluation of the Data Evidence based decisions Applicability of extrapolation –for example can toxicities seen with intravenous preparations of 6-mercaptopurine be applicable to oral preparations? –Can complications of patients that have received one type of therapy, for example intracranial radiation or particular combinations and sequences of chemotherapy, be considered to represent patients that have not received that particular therapy?

15. Not at Issue Rationale for pharmacogenetic testing in general Rationale for individualization of dosing to minimize risk

16. International Cooperation “To proceed, science must cross boundaries” –Susan Band Horwitz, President American Association of Cancer Research, July 11, 2003 Pediatric Oncology is a set of diseases with about 13000 new cases per year in the United States To complete studies in a timely manner and to effectively use limited resources, international cooperation is necessary The FDA is issuing Written Requests for pediatric oncology studies with time limits to improve access to investigational drugs and stimulate clinical research

17. International Cooperation For international studies to proceed in a timely manner, regulatory requirements must be consistent Regulatory requirements that pertain to study initiation and study monitoring have been perceived as barriers Note that pediatric oncology studies may or may not be intended for registration of a marketing claim, but are most often initiated to define optimum therapy for a particular population

18. International Cooperation Seeking recommendations on how to achieve consistency and minimize barriers